Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death

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Titel: Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death
Autor(en): Cabukusta, Birol
Nettebrock, Niclas T.
Kol, Matthijs
Hilderink, Angelika
Tafesse, Fikadu G.
Holthuis, Joost C. M.
Zusammenfassung: Ceramides are essential precursors of sphingolipids with a dual role as mediators of apoptotic cell death. Previous work revealed that the ER-resident ceramide phosphoethanolamine (CPE) synthase SMSr/SAMD8 is a suppressor of ceramide-mediated apoptosis in cultured cells. Anti-apoptotic activity of SMSr requires a catalytically active enzyme but also relies on the enzyme’s N-terminal sterile α-motif or SAM domain. Here, we demonstrate that SMSr itself is a target of the apoptotic machinery. Treatment of cells with staurosporine or the death receptor ligand FasL triggers caspase-mediated cleavage of SMSr at a conserved aspartate located downstream of the enzyme’s SAM domain and upstream of its first membrane span. Taking advantage of reconstitution experiments with SMSr produced in a cell-free expression system, specific caspase-inhibitors and gene silencing approaches, we show that SMSr is a novel and specific substrate of caspase-6, a non-conventional effector caspase implicated in Huntington’s and Alzheimer’s diseases. Our findings underscore a role of SMSr as negative regulator of ceramide-induced cell death and, in view of a prominent expression of the enzyme in brain, raise questions regarding its potential involvement in neurodegenerative disorders.
Bibliografische Angaben: Bioscience Reports 37(4) 2017
URL: https://repositorium.ub.uni-osnabrueck.de/handle/urn:nbn:de:gbv:700-2018010516506
Schlagworte: aptoptosis; caspases; membrane biochemistry; sphingolipids
Erscheinungsdatum: 5-Jan-2018
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